Address by the Honorary Founding President of the Xenotransplantation Society. The eye of an eagle: xenobiology and the quest for bioadvantage.

My purpose in these remarks is to stimulate us to consider the vast array that nature has provided us in the differentiation of species, and to examine the possibility that some of these differences might prove useful in other species, including man.

Volume-outcome relationships in cardiovascular operations: New York State, 1990-1995.

BACKGROUND: It has been known for nearly 20 years that, in cardiovascular operations, a significant inverse relationship exists between clinical outcomes and the volume of procedures performed. Interestingly, this relationship persists 2 decades after it was recognized. OBJECTIVE: The purpose of this study was to examine the relationship between hospital volume and in-hospital deaths in 3 cardiovascular procedures: coronary artery bypass grafting, elective repair of abdominal aortic aneurysms, and repair of congenital cardiac defects. METHODS: The database includes all patients who were hospitalized in New York State during the years 1990 to 1995. Using standard logistic regression techniques, we analyzed the relationship between hospital volume and outcome. RESULTS: No correlation exists between hospital volume and in-hospital deaths in coronary artery bypass grafting. Statewide, 31 hospitals performed 97,137 operations over the 6-year period (overall mortality rate, 2. 75%). By contrast, most of the hospitals statewide (195 of 230 hospitals) performed 9847 elective abdominal aortic aneurysm repairs with an overall mortality rate of 5.5%. In abdominal aortic aneurysm operations, a significant inverse relationship between hospital volume and in-hospital deaths was determined. Sixteen hospitals performed 7199 repairs for congenital cardiac defects. A significant inverse relationship (which was most pronounced for neonates) was found between volume and death. CONCLUSIONS: The importance of these findings lies in the rather striking difference between the volume-outcome relationship found for operations for abdominal aortic aneurysms and congenital cardiac defects and the lack of such a relationship for coronary artery bypass grafting. This observation may be largely explained by the quality improvement program in New York State for bypass operations since 1989. If so, these results have important implications for expanding the scope of quality improvement efforts in New York State.

Cost-effectiveness of coronary artery bypass surgery in octogenarians.

OBJECTIVE: The objective of this retrospective cohort study was to determine whether coronary artery bypass graft (CABG) surgery is effective and cost-effective relative to medical management of coronary artery disease (CAD) in the elderly. SUMMARY BACKGROUND DATA: The aging of the U.S population and the improvements in surgical techniques have resulted in increasing numbers of elderly patients who undergo this surgery. The three randomized, controlled trials (RCTs) that established the efficacy of CABG surgery completed patient enrollment from 19 to 24 years ago excluded patients older than 65 years. Although information regarding outcomes of CABG in this population is mainly available in case series, a major lacuna exists with respect to information on quality of life and cost effectiveness of surgery as compared with medical management. METHODS: The authors retrospectively formed surgical and medically managed cohorts of octogenarians with significant multivessel CAD. More than 600 medical records of patients older than 80 years who underwent angiography at our institution were reviewed to identify 48 patients who were considered reasonable surgical candidates but had not undergone surgery. This cohort was compared with 176 patients who underwent surgery. RESULTS: The cost per quality-adjusted life year saved was $10,424. At 3 years, survival in the surgical group was 80% as compared with 64% in the entire medical cohort and 50% in a smaller subset of the medical cohort. Quality of life in patients who underwent surgery was measurably better than that of the medical cohort with utility index scores, as measured by the EuroQoL, (a seven-item quality of life questionnaire) of 0.84, 0.61, and 0.74, respectively. CONCLUSIONS: Performing CABG surgery in octogenarians is highly cost-effective. The quality of life of the elderly who elect to undergo CABG surgery is greater than that of their cohorts and equal to that of an average 55-year-old person in the general population.

Implantable left ventricular assist devices: an evolving long-term cardiac replacement therapy.

OBJECTIVE: The authors' 8-year experience with both inpatient and outpatient left ventricular assist device (LVAD) support is presented to show the possibilities and limitations of long-term outpatient mechanical circulatory assistance. SUMMARY BACKGROUND DATA: The limitation of suitable cardiac donors has led to the use of LVADs as a temporizing measure for patients awaiting cardiac transplantation. The success of such devices in the short and medium term as a bridge to transplantation has led to their evaluation as a long-term destination therapy for end-stage heart disease. METHODS: Between August 1990 and February 1997, 85 patients with end-stage heart disease underwent insertion of implantable LVADs. Fifty-two patients underwent pneumatic device insertion and 32 patients received a vented electric device. RESULTS: Patients were supported for a mean of 109+/-13 days for an overall survival to transplant (54) or explant (3) of 73%. Nineteen patients were discharged from the hospital on a mean of postoperative day 41+/-4 (range, 17-68) for an outpatient support time of 108+/-30 days (range, 2-466). Of 12 patients supported after postcardiotomy cardiogenic shock, 10 (82%) survived to hospital discharge. Perioperative right ventricular failure was treated in most patients with inotropic agents and inhaled nitric oxide with only six patients requiring right ventricular assist device support. Thromboembolic rate was low (0.016 events/patient-month) despite minimal or no anticoagulation in all cases. CONCLUSIONS: Left ventricular assist device support has evolved to become an outpatient therapy with excellent survival rates and an acceptable morbidity. Accordingly, wearable LVADs should be studied as permanent treatment options for patients who are not transplant candidates.

Using surgical outcomes data.

The measurement of expanded outcomes data is continuing. As managed care continues to spread through the United States and competition increases, an increased emphasis will be placed on the importance of collecting and analyzing outcomes data as a way to assess and ensure quality of care. Surgeons must familiarize themselves with the concepts behind the measurement of outcomes data and involve themselves in the development of outcomes indicators for surgery in order to ensure a continuing high level of surgical care is provided to their patients.

Outcomes assessment: a primer.

The routine assessment of outcomes, including clinical and functional outcomes, charges, cost and effectiveness data, and complications of treatment, as well as HRQOL and patient satisfaction, are essential to demonstrate and ensure the quality of care. Secondary to patient-related concerns, outcomes data provide a tool for use by the surgeon in proving (and improving) the quality of care rendered. These tools, as well as surgical input into the development of outcomes indicators, will allow surgeons to practice more effectively in a managed care environment.

Assessment of submaximal exercise capacity in patients with left ventricular assist devices.

BACKGROUND: Long-term implantable left ventricular assist devices (LVADs) are increasingly used as a bridge to cardiac transplantation and may be used as long-term therapy for end-stage heart failure. After insertion of an LVAD, patients frequently become ambulatory. Sensors contained within these devices can measure the hemodynamic demands of submaximal exercise. In this study, we performed serial assessment of submaximal exercise capacity in patients with LVADs early (< 3 months), mid (3 to 6 months), and late (> 6 months) after device implantation to determine whether submaximal exercise capacity increased over time and whether this was related to improvements in the cardiac output response. Moreover, we compared the sub-maximal exercise capacities of these patients with those of normal subjects and patients with mild to severe heart failure. METHODS AND RESULTS: An encouraged 6-minute walk test with metabolic measurements was used to assess submaximal exercise capacity in 14 patients with LVADs, 20 patients with mild to moderate congestive heart failure (CHF), 14 patients with severe heart failure dependent on dobutamine (DB), and 6 normal subjects. Cardiac output measurements at rest and during exercise were obtained in the patients with devices. Distance walked was significantly greater for LVAD patients than DB patients and was similar to that for patients with mild CHF (LVAD, 1562 +/- 404; DB, 948 +/- 241; and CHF, 1358 +/- 278 ft; P < .01). Vo2 was also greater in the LVAD than DB or CHF patients (LVAD, 16.3 +/- 6.5; DB, 9.8 +/- 4.8; and CHF, 11.2 +/- 2.0 mL.kg-1.min-1; P < .05). Vo2 (23.4 +/- 7.4 mL.kg-1.min-1) and distance walked (2142 +/- 408 ft) in normal subjects was significantly greater than for all patient groups (all P < .01). Serial assessment of submaximal exercise capacity in LVAD patients demonstrated continued sustained improvement over time (early, 1261 +/- 341; mid, 1538 +/- 345; and late, 1867 +/- 265 ft; P < .05). However, peak cardiac output response was unchanged (early, 8 +/- 1.3; mid, 8.6 +/- 1.4; and late, 8.6 +/- 1.4 L/min; P = NS). CONCLUSIONS: The submaximal exercise capacity of LVAD patients is comparable to that of patients with mild CHF but significantly better than that of dobutamine-dependent patients. Hemodynamic and metabolic assessment during 6-minute walk tests demonstrates that in patients with heart failure and LVAD, cardiovascular demands are generally > 85% of maximum. A significant sustained improvement in submaximal exercise capacity occurs with chronic LVAD therapy. Lack of alteration of the cardiac output response to exercise suggests that this functional improvement results from peripheral mechanisms.

Multivariate analysis of factors affecting waiting time to heart transplantation.

BACKGROUND: The growing clinical success of cardiac transplantation has resulted in a dramatic increase in the number of patients referred and subsequently listed for cardiac transplantation. Paradoxically, in the presence of a limited donor organ pool, such expansion has increased both the waiting time for transplantation and the number of patients dying while on the waiting list. METHODS: We performed univariate and multivariate analyses of the waiting times of 301 patients listed for transplantation using a Cox proportional hazards model to evaluate the simultaneous effect of multiple variables on the waiting time of heart transplant candidates. Variables considered included age, sex, race, blood type, weight at listing, United Network for Organ Sharing (UNOS) status at listing, UNOS status at transplantation, and proportion of time on the waiting list as UNOS status 1. RESULTS: The mean waiting time for patients ultimately having transplantation was 170.2 +/- 206.0 days; the median waiting time was 103.5 days. Age, sex, weight, blood type, and percent of time as UNOS status 1 all had a significant impact on waiting time in the univariate analysis. By multivariate analysis, proportion of time as UNOS status 1, lower weight at listing, and blood type AB were all highly associated as predictors of a shorter waiting time. Weight at listing represented a continuous variable whose risk ratio for a shorter waiting time correlated in such a way that the risk of a longer waiting time increased 2.3 per 22.5-kg (50-pound) increase in weight. Blood types A and B, although associated with a shorter waiting time, correlated less strongly than the other three variables. CONCLUSIONS: Our findings from this multivariate analysis demonstrate that UNOS status, blood type, and weight were the variables that most strongly affected overall waiting time for transplantation. It is our hope to define more accurately a group of patients with both a high likelihood of a long waiting time and a prohibitive risk of death while on the waiting list, who therefore may benefit from surgical alternatives to transplantation.

Supporting future surgical innovation. Lung transplantation as a case study.

OBJECTIVE: Using lung transplantation as a case study, this article addressed the problem of supporting innovative clinical surgery in an era of increasing pressures for cost containment. SUMMARY BACKGROUND DATA: After sporadic attempts at lung transplantation during the 1960s and 1970s, its clinical development began in earnest during the early 1980s. As a result of a wide range of incremental advances, the results have improved significantly. The Health Care Financing Administration, however, has not yet issued a national policy covering lung transplants and has left the coverage decision to the discretion of its regional contractors. METHODS: The authors surveyed the major commercial insurers, the Blue Cross Blue Shield Association, and a sample of Medicare intermediaries to evaluate the coverage of lung transplantation. They also interviewed the National Heart, Lung, and Blood Institute and industrial firms about their support for clinical research. RESULTS: Government and industry funding were limited, and the development and assessment of lung transplants have been financed predominantly by academic institutions through cross-subsidization from patient care and teaching funds. The major private payers and Blue Cross Blue Shield decided to cover this procedure in the early 1990s. Coverage decisions by Medicare intermediaries, however, revealed considerable variability. Moreover, the absence of a specific diagnosis-related group for lung transplants had considerable consequences for institutions in all-payer states, in which payments appeared to be considerably lower than the mean costs of a transplant procedure (about $110,000). CONCLUSIONS: This analysis indicated that there was a growing disparity between the increasing demand for outcomes data about new procedures and the limited resources available for supporting the development and assessment of new operations. It this disparity is not addressed, the rate of surgical innovation may be jeopardized, and timely outcomes data may not be acquired. It was concluded that provisional coverage within a predetermined research protocol may be a promising mechanism to remedy this situation, providing timely assessment of new procedures before widespread application.

Effect of anti-HLA antibodies on the long-term survival of heart and kidney allografts.

Study of anti-HLA antibodies in a population of 238 primary renal and 199 primary heart allograft recipients showed significant association between development of anti-HLA antibodies and that of chronic allograft rejection. The 5-year renal allograft survival was 70% in recipients without antibodies and 53% in recipients who developed anti-HLA alloantibodies during the first year following transplantation. Heart allograft survival at 5 years was 91% in patients without and 78% in patients with antibodies during the first 12 months posttransplantation. Development of antibodies is associated with acute rejection episodes and probably with the release of soluble HLA antigens.

Sixteen years of cardiac transplantation: the Columbia Presbyterian Medical Center experience 1977 to 1993.

Cardiac transplantation is currently recognized as the best therapy available for the treatment of endstage heart disease. Since 1977, more than 650 cardiac transplants have been performed at CPMC, with a one-year survival rate currently approaching 85% and a 5-year survival rate approaching 65%. Throughout the 16-year experience with cardiac transplantation at CPMC, the criteria of eligibility for both donor and recipient candidates have been expanded to include older patients. In addition, pediatric patients requiring complex arterial or venous reconstruction and patients with elevated, but reversible pulmonary vascular resistance have been transplanted with excellent results. With the evolution of prolonged posttransplant survival has come a new group of complications associated with chronic long-term immunosuppressive therapy. These, and issues relating to cardiac retransplantation, continue to increase, largely because of the critical lack of organ donors. Continued efforts are being developed to optimize and reduce the total amount of immunosuppression administered postoperatively. Currently, research interests at CPMC include therapy for transplant coronary artery disease, left ventricular assist devices, and xenotransplantation. Ongoing investigations in these and other areas of transplantation have been established to encourage continued growth both within the field and at CPMC through the 21st century.

Effect of recipient gender and race on heart and kidney allograft survival.

Study of long-term survival of heart allografts shows that AA males and females have lower graft survival rates than those observed in NAC recipients. Primary kidney allografts in AA males, but not females, also display lower 5-year survival rates compared to those observed in the corresponding populations of NAC. Comparison of graft survival in the overall population of male and female recipients of kidney allografts shows that females have higher graft survival rates, probably as a result of better HLA matching. The level of alloantibody activity in posttransplantation sera is similar in the two populations, suggesting that factors other than HLA mismatching may contribute to the higher degree of graft failure in AA recipients.

Management of peripheral vascular problems in recipients of cardiac allografts.

Five hundred and twenty consecutive heart transplant cases (458 adult, 62 pediatric) were reviewed to assess the impact of peripheral vascular problems. Peritransplant interventions requiring vascular cannulation (e.g., intraaortic balloon pump procedures, catheterization of the right and left sides of the heart, femoral bypass) resulted in 10 complications that necessitated nine surgical procedures. Five aortic aneurysms (three infrarenal and two suprarenal) were resected. There was one death unrelated to the aneurysm resection. Sixteen patients had evidence of peripheral vascular disease (PVD). There were three deaths in this group, none directly related to the PVD. Three patients required vascular reconstruction (axillobifemoral, bilateral femoral distal and popliteal endarterectomy) in the posttransplant period, all for advanced ischemic symptoms. Except for one patient in whom ischemia-related ulcers developed on the heels, all patients had improved or stable symptoms that did not require intervention. There were no limb losses or vascular infections. We conclude that despite the rigors of posttransplant immunosuppression, patients with stable manifestations of PVD may successfully undergo heart transplantation and subsequent vascular reconstruction, when indicated, without prohibitive risk.

Evaluation of surgical procedures. Changing patterns of patient selection and costs in heart transplantation.

During the past 4 years we have observed a marked increase in costs of heart transplantation in our center. This trend coincides with a shift in our recipient population toward the more severely ill patients. The percentage of patients bound for the intensive care unit has doubled. In analyzing the components of cost, we find that the length of stay, both in special care and regular nursing units, accounts for most of the cost increase. In our study of outcomes we find no significant difference in survival, at 1 month and 1 year, between recipients operated on from the intensive care unit and those not in intensive care. We find that at 1 year after transplantation, approximately 80% of patients are rehabilitated, which we define as the ability to work or to go to school. Only 20% of patients are off disability rolls, however, primarily because of problems related to insurance and the cost of continuing care, including drugs. We conclude that the comprehensive evaluation of surgical procedures requires an approach that balances costs with results on a continuing and long-term basis.

Vascular (humoral) rejection in human cardiac allograft biopsies: relation to circulating anti-HLA antibodies.

Vascular or humoral rejection (as defined by linear deposits of immunoglobulin and complement in myocardial capillaries) and the presence of circulating lymphocytotoxic anti-HLA antibodies are each associated with reduced long-term graft or patient survival. The relationship between these two factors has not been determined. We used immunofluorescent techniques to study 46 cardiac biopsy specimens in 16 patients from 15 to 412 days after transplantation. Biopsy specimens were selected from the first 2 months, and at approximately 6 and 12 months after transplantation and did not include episodes of acute cellular rejection. Each specimen studied was compared to a serum sample drawn an average of 1.8 days (range, 0 to 9 days) from the time of biopsy to assay for circulating anti-HLA antibodies. Of the specimens obtained at or near a positive anti-HLA antibody test, 90% (27 of 30) were found to have linear deposits of immunoglobulin (not necessarily with complement) versus 75% (12 of 16) of specimens obtained at the time of a negative test. Twenty-one cases of vascular rejection were documented. Both immunoglobulin M and immunoglobulin G were deposited along with complement in 13 instances; immunoglobulin M and complement were deposited in eight cases; no case had only immunoglobulin G and complement. The presence of circulating anti-HLA antibody in the serum was associated with 14 of the 21 cases of vascular rejection. Linear deposits of immunoglobulin in the capillaries of myocardium were frequently observed when anti-HLA antibodies were present in the serum.(ABSTRACT TRUNCATED AT 250 WORDS)